Attorney Ref. 79532.8(I03.US(IZ
`
`ABSTRACT
`
`technique to adjust the dosage ofa nitrogen scavenging drug. determine whether to administer a
`
`1 8
`
`The present disclosure provides methods for evaluating daily ammonia exposure based
`
`on a single fasting ammonia blood level measurement, as well as methods that utilize this
`
`nitrogen scavenging drug, and treat nitrogen retention disorders.
`
`TGSSZ—RWD.L'SUIHJLGALJZFHQUSJ
`
`EXO
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`1 of 210
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`Electronic Acknowledgement Receipt
`
`
`
`Application Number: 13417137
`
`International Application Number:
`
`Confirmation Number:
`
`Title of Invention:
`
`MEI'HODS 0F THERAPEUTIC MONFTORING OF NITROGEN SCAVENGING
`DRUGS
`
`Charge any Additional Fees required under 37 CPR. Section 1.17 (Patent application and reexamination processing fees)
`
`$1025
`Payment was successfully received in RAM
`
`RAM confirmation Number 6954
`
`First Named lnventorlApplicant Name:
`
`Bruce SCHARSCHMIDT
`
`34055
`Customer N um ber:
`
`
`Patrick D. Morrisz’Colleen Kirchner
`Filer:
`
`
`Filer Authorized By:
`
`Patrick D. Morris
`
`
`
`Receipt Date: 09—MAR—2012
`
`Filing Date:
`
`Time Stamp:
`
`20:28:09
`
`Application Type:
`
`Utility under 35 USC 11 Ha}
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`Submitted with Payment
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`502586
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`Charge anyI Additional Fees required under 3? C.F.R. Section 1.19iDocument supply fees)
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`Attorney Ref. 79532.8003.US(I2
`
`What is claimed is:
`
`I.
`
`A method for determining whether to increase a dosage ofa nitrogen scavenging
`
`drug in a subject currently receiving the nitrOgen scavenging drug, comprising:
`
`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level to determine whether to increase the dosage of a nitrogen scavenging drug,
`
`wherein the dosage needs to be increased if the fasting blood ammonia level is greater than half
`
`the upper limit of normal for blood ammonia level.
`
`2.
`
`A method for determining whether to administer a nitrogen scavenging drug to a
`
`subject having a nitrogen retention disorder comprising:
`
`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level to detelrnine whether to administer a nitrogen scavenging drug to the subject,
`
`wherein a nitrogen scavenging drug needs to be administered to the subject if the fasting blood
`
`ammonia level is greater than half the upper limit of normal for blood ammonia level.
`
`3.
`
`A method of treating a subject with a nitrogen retention disorder who has
`
`previously been administered a nitrogen scavenging drug comprising:
`
`a) measuring a fasting blood ammonia level for the subject; and
`
`b) comparing the fasting blood ammonia level to the upper limit of normal for blood
`
`ammonia level and administering an increased dosage of the nitrogen scavenging drug if the
`
`fasting blood ammonia level is greater than half the upper limit of normal for blood ammonia
`
`level.
`
`4.
`
`The method of claim 1. further comprising:
`
`c') administering an increased dosage of the nitrogen scavenging drug if the need exists.
`
`5.
`
`The method of any of claims 13, wherein the nitrogen retention disorder is
`
`selected from the group consisting of a urea cycle disorder and hepatic encephalopathy.
`
`6.
`
`The method of any of claims 13, wherein the nitrogen scavenging drug is a PAA
`
`179532—8003 .USU IHIGMJZF l 49(l5 .l
`
`consisting of glycery] tri-[4—phenylbutyrate] ('HPN-lOO). phenylbutyric acid (PBA), sodium PBA
`
`prodrug.
`
`7.
`
`The method of claim 6, wherein the FAA prodrug is selected from the group
`
`(NaPBA), and a combination of two or more of HPN-lDO, FHA, and NaPBA.
`
`5 of 210
`
`

`

`10.
`
`The method of any of claims 1-3, further comprising the step of determining an
`
`upper limit of normal for blood ammonia level for the subject prior to step (b).
`
`ll.
`
`The method of any of claims 1-3, wherein the upper limit of normal blood
`
`ammonia level is 35 umoUL.
`
`12.
`
`The method of claim 6, further comprising:
`
`c) measuring urinary PAGN excretion; and
`
`e) determining an effective dosage of the PAA prodrug based on a mean conversion of
`
`PAA prodru g to urinary PAGN of 60—75%.
`
`Attorney Ref. 79532.8003.US(I2
`
`8.
`
`The method of any of claims 13, wherein the nitrogen scavenging drug is sodium
`
`benzoate.
`
`9.
`
`The method of claim 3 or 4, wherein administering an increased dosage of the
`
`nitrogen scavenging drug produces a normal average daily ammonia level in the subject.
`
`ESE—8003 .L'SfllfLEGALl'l? l 49%.]
`
`6 of 210
`
`

`

`NH ‘ I
`L
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`“V5.
`
`“532—8003 .130 lfLEGALl 27 l 4905.]
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`[i r magnum:
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`ma
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`
`muu‘ciuam
`
`immxlum-snmd u * '
`2: 531mm:
`
`_?Hausa-:23:
`
`Figure l
`
`Attorney Ref. 79532300311502
`
`:“figfilifllir
`'
`
`3..-
`
`P M
`
`adam
`
`7 of 210
`
`

`

`Attorney Ref. 79532.8003.US(I2
`
`E-Ox,............... ..........................................:.:......................................................................7:................................. n
`10.9
`20.9
`35.0
`43.0
`50.9
`60.0
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`.
`90.0
`103.0
`
`110.0:
`
`Figure 2
`
`33
`
`7" ""éé‘HéaSunQ Ammmza mama Ammania 0-24 hams
`Linear Hegressim and 95% ci cf Prafliafim
`A?! Studies combined“ 55 unim subij
`
`T9532—fim3f501fLEGAL327HDUSJ
`
`8 of 210
`
`

`

`Figure 3
`
`A.
`
`Attorney Ref. 79532300311802
`
`
`
`
`
`
`
`12hr
`
`16%»
`
`was
`
`24hr
`
`{15?}
`“W Napfifl
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`
`"19532—3003 .L’Sfl ULEGALZ 27 l 4905.]
`
`9 of 210
`
`

`

`Electronic Acknowledgement Receipt
`
`
`
`Application Number: 13417137
`
`International Application Number:
`
`Confirmation Number:
`
`Title of Invention:
`
`MEI'HODS 0F THERAPEUTIC MONFTORING OF NITROGEN SCAVENGING
`DRUGS
`
`Charge any Additional Fees required under 37 CPR. Section 1.17 (Patent application and reexamination processing fees)
`
`$1025
`Payment was successfully received in RAM
`
`RAM confirmation Number 6954
`
`First Named lnventorlApplicant Name:
`
`Bruce SCHARSCHMIDT
`
`34055
`Customer N um ber:
`
`
`Patrick D. Morrisz’Colleen Kirchner
`Filer:
`
`
`Filer Authorized By:
`
`Patrick D. Morris
`
`
`
`Receipt Date: 09—MAR—2012
`
`Filing Date:
`
`Time Stamp:
`
`20:28:09
`
`Application Type:
`
`Utility under 35 USC 11 Ha}
`
`Payment information:
`
`Submitted with Payment
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`Payment Type Deposit Account
`
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`The Director ofthe USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
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`MEI'HODS OF THERAPEUTIC MONiTORlNG 0F NITROGEN SCAVENGING
`DRUGS
`
`
`
`First Named InventorIApplica nt Name:
`
`Bruce SCHARSCHMIDT
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`Title of Invention METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
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`16 of 210
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`

`

`Attorney Ref. 79532.8003.USII‘2
`
`METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING
`
`DRUGS
`
`RELATED APPLICATIONS
`
`[0001] The present application claims the benefit ofU.S. Provisional Application No.
`
`61/564668. filed November 29. 2011. and US. Provisional Application No. 61/541100. filed
`
`September 30, 2011. the disclosures of which are incorporated by reference herein in their
`
`entirety, including drawings.
`
`BACKGROUND
`
`[0002] Nitrogen retention disorders associated with elevated ammonia levels include urea cycle
`
`79532—3003 .US‘U li'LEGALJZF l 4905.]
`
`disorders (UCDS) and hepatic encephalOpathy (HE).
`
`[0003] UCDS include several inherited deficiencies of enzymes or transporters necessary for
`
`the synthesis of urea from ammonia, including enzymes involved in the urea cycle. The urea
`
`cycle is depicted in Figure l. which also illustrates how certain ammonia-scavenging drugs act to
`
`assist in elimination of excessive ammonia. With reference to Figure l. N-acetyl glutamine
`
`synthetase (NAGS)-derived N—acetylglutamate binds to carbamyl phosphate synthetase (CPS).
`
`which activates CPS and results in the conversion of ammonia and bicarbonate to carbamyl
`
`phosphate.
`
`In turn, carbarnyl phosphate reacts with ornithine to produce citrulline in a reaction
`
`mediated by ornitbine transcarbamylase (OTC). A second molecule of waste nitrogen is
`
`incorporated into the urea cycle in the next reaction. mediated by arginosuccinate synthetase
`
`(ASS). in which citrulline is condensed with aspartic acid to form argininosuccinic acid.
`
`Argininosuccinic acid is cleaved by argininosuccinic lyase (ASL) to produce arginine and
`
`fumarate.
`
`In the final reaction of the urea cycle. arginase (ARG) cleaves arginine to produce
`
`omithine and urea. Of the two atoms of nitrogen incorporated into urea, one originates from free
`
`ammonia (N HI) and the other from aspartate. UCD individuals born with no meaningful
`
`residual urea synthetic capacity typically present in the first few days oflife (neonatal
`
`presentation). Individuals with residual function typically present later in childhood or even in
`
`adulthood. and symptoms may be precipitated by increased dietary protein or physiological
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`stress {e.g.. intercun-ent illness}.
`
`[0004] Hepatic encephalopathy (HE) refers to a spectrum of neurologic signs and symptoms
`
`believed to result from hyperammonemia, which frequently occur in subjects with cirrhosis or
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`Attorney Ref. 79532.8003.US(I2
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`certain other types of liver disease. Subjects with HE typically show altered mental status
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`ranging from subtle changes to coma, features similar to subjects with UCDs.
`
`[0005] Subjects with nitrogen retention disorders whose ammonia levels andfor symptoms are
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`not adequately controlled by dietary restriction of protein andfor dietary supplements are
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`generally treated with nitrogen scavenging agents such as sodium phenylbutyrate (N aPBA,
`
`benzoate. These are often referred to as alternate pathway drugs because they provide the body
`
`with an alternate pathway to urea for excretion of waste nitrogen (Brusilow 1930: Brusilow
`
`1991). NaPBA is a phenylacetic acid (PAA) prodrug. Another nitrogen scavenging drug
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`currently in development for the treatment of nitrogen retention disorders is glyceryl tri—[4—
`
`phenylbutyrateflHPNd00), which is described in US. Patent No. 5,963,979. HPNJUO, which is
`
`commonly referred to as GT4P or glycerol PBA, is a prodrug of PBA and a pre—prodrug of PAA.
`
`[0006] HPN—IOD and NaPBA share the same general mechanism of action: PBA is converted
`
`to PAA via beta oxidation. and FAA is conjugated enzymatically with glutamine to form
`
`phenylacetylglutamjne (PAGN). which is excreted in the urine. The structures of PBA. FAA,
`
`and PAGN are set forth below.
`
`approved in the United States as BUPHENYL® and in Europe as AMMONAPS®j or sodium
`
`ESE—3003 .USU lfLEGALl'l? l 4905.]
`
`j’ “m “\‘N/m‘cesaa‘
`
`on or; ylbuty rate
`
`tr'
`
`_
`
`Phenyiacetéc acid
`
`sag
`
`H
`
`a
`
`If”?
`
`Pneayéasetng-tutamine
`
`[0007] The clinical benefit of NaPBA and HPN—IUO with regard to nitrogen retention disorders
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`derives from the ability of PAGN to effectively replace urea as a vehicle for waste nitrogen
`
`excretion andfor to reduce the need for urea synthesis (Brusilow 1991; Brusilow 1993). Because
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`Attorney Ref. 79532300311802
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`each glutamine contains two molecules of nitrogen, the body rids itself of two waste nitrogen
`
`atoms for every molecule of PAGN excreted in the urine. Therefore, two equivalents of nitrogen
`
`are removed for each mole of PAA converted to PAGN. PAGN represents the predominant
`
`terminal metabolite, and one that is stoichiometrically related to waste nitrogen removal. 3
`
`measure of efficacy in the case of nitrogen retention states. The difference between HPN-IOO
`
`and NaPBA with respect to metabolism is that HPN- 100 is a triglyceride and requires digestion,
`
`presumably by pancreatic lipases, to release PBA (McGuire 2010).
`
`[0008]
`
`In contrast to NaPBA or HPN-lOO, sodium benzoate acts when benzoic acid is
`
`combined enzymatically with glycine to form hippuric acid. For each molecule of hippuric acid
`
`excreted in the urine, the body rids itself of one waste nitrogen atom.
`
`[0009] Methods of determining an effective dosage of PAA prodrugs such as NaPBA or HPN—
`
`100 for a subject in need of treatment for a nitrogen retention disorder are described in
`
`WOOQ/l 134460 and WOW/025303. Daily ammonia levels. however. may vary greatly in a
`
`subject. This can lead to overestimation by the physician of the average daily ammonia levels.
`
`which may result in overtreatment. Thus, there is a need in the art for improved methods for
`
`PAA prodrug dose determination and adjustment based on ammonia levels in subjects with
`
`i‘JSJE—fiflffi .USU li'LEGALlZ? l 4905 .l
`
`measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the
`
`nitrogen retention disorders such as UCDs or HE.
`
`W
`
`[0010] Provided herein in certain embodiments are methods for determining whether to
`
`increase a dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder by
`
`upper limit of normal (ULN) for blood ammonia. where a fasting blood ammonia level that is
`
`greater than half the ULN for blood ammonia indicates that the dosage needs to be increased.
`
`In
`
`certain embodiments. the nitrogen retention disorder is a UCD or HE.
`
`In certain embodiments,
`
`the nitrogen scavenging drug is HPNilUU. PBA, NaPBA, sodium benzoate. or any combination
`
`thereof(i.e., any combination of two or more of HPN—IDO. PBA. NaPBA).
`
`In certain
`
`embodiments. the ULN is around 35 umol/L or 59 ug/mL.
`
`In certain embodiments the methods
`
`include an additional step of administering an increased dosage of the nitrogen scavenging drug
`
`if the need exists. and in certain of these embodiments administration of the nitrogen scavenging
`
`drug produces a normal average daily ammonia level in the subject.
`
`In certain embodiments
`
`wherein a determination is made to administer an increased dosage of nitrogen scavenging drug
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`Attorney Ref. 7953230031502
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`and wherein the nitrogen scavenging drug is a PAA prodrug, the methods include an additional
`
`step of measuring urinary PAGN excretion and determining an effective dosage of the FAA
`
`prodmg based on a mean conversion of PAA prodrug to urinary PAGN of 60—75%.
`
`[001]] Provided herein in certain embodiments are methods for determining whether to
`
`administer a nitrogen scavenging drug to a subject with a nitrogen retention disorder by
`
`measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the.
`
`ULN for blood ammonia, where a fasting blood ammonia level that is greater than half the ULN
`
`for blood ammonia indicates that the nitrogen scavenging drug needs to be administered.
`
`In
`
`certain embodiments, the nitrogen retention disorder is a UCD or HE.
`
`In certain embodiments,
`
`the nitrogen scavenging dtug is HPN—IOU, PBA. NaPBA. sodium benzoate, or any combination
`
`thereof(i.e_, any combination of two or more of HPN—IUO, PBA, NaPBA).
`
`In certain
`
`embodiments. the ULN is around 35 ttmollL or 59 ttgme.
`
`In certain embodiments, the methods
`
`include an additional step of administering a nitrogen scavenging drug if the need exists, and in
`
`certain of these embodiments administration of the nitrogen scavenging drug produces a normal
`
`average daily ammonia level in the subject.
`
`In certain embodiments wherein a determination is
`
`made to administer a nitrogen scavenging drug and wherein the nitrogen scavenging drug is a
`
`PAA pl‘odrug. the methods further include a step of determining an effective initial dosage of the
`
`7’9532—8003 .USU IHIGALJZI l 49il5 .l
`
`PAA prodru g by determining a target urinary PAGN output based on a target nitrogen output and
`
`calculating an effective initial dosage that results in the target urinary PAGN output based on a
`
`mean conversion of PAA prodrug to urinary PAGN of 60—75%.
`
`In certain embodiments, the
`
`methods include a step of administering the calculated effective initial dosage.
`
`[0012] Provided herein in certain embodiments are methods for treating a nitrogen retention
`
`disorder in a subject who has previously been administered a nitrogen scavenging drug by
`
`measuring a fasting blood ammonia level, comparing the fasting blood ammonia level to the
`
`ULN for blood ammonia, and administering an increased dosage of the nitrogen scavenging dmg
`
`if the fasting ammonia level is greater than half the ULN for blood ammonia.
`
`In certain
`
`embodiments, administration of an increased dosage of the nitrogen scavenging drug produces a
`
`normal average daily ammonia level in the subject.
`
`In certain embodiments, the nitrogen
`
`retention disorder is a UCD or HE.
`
`In certain embodiments, the nitrogen scavenging drug is
`
`HPN -100. PBA, NaPBA. sodium benzoate. or any combination thereof (i.e., any combination of
`
`two or more of HPN-lOO, PBA, NaPBA).
`
`In certain embodiments, the ULN is around 35
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`umolfL or 59 tLg/mL.
`
`In certain embodiments wherein the nitrogen scavenging drug is a FAA
`
`prodlug, the methods include an additional step of measuring urinaiy PAGN excretion and
`
`determining an effective dosage of the FAA prodru g based on a mean conversion of PAA
`
`prodrug to urinary PAGN of 604570.
`
`In certain embodiments, the methods include a step of
`
`administering the calculated effective. dosage.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`[0013] Figure l: The urea cycle and how certain nitrogen-scavenging drugs may assist in
`
`elimination of excessive anunonia.
`
`[0014]
`
`Figure 2: Relationship between fasting ammonia and average ammonia UCD patients.
`
`[0015] Figure 3: Venous blood ammonia values over 24 hours in (A) adult and (B) pediatric
`
`UCD patients.
`
`
`DETAILED DESCRIPTION
`
`179532—8003 .USU IHIGMJZF l 4905 .l
`
`confounded by the fact that individual ammonia values vary several—fold over the course of a day
`
`[0016] The following description of the invention is merely intended to illustrate. various
`
`embodiments of the invention. As such, the specific modifications discussed are not to be
`
`construed as limitations on the scope of the invention. It will be apparent to one skilled in the art
`
`that various equivalents, changes, and modifications may be made without departing from the
`
`scope of the invention, and it is understood that such equivalent embodiments are to be included
`
`herein.
`
`[0017]
`
`In subjects with a nitrogen retention disorder, the desired effect of treatment with a
`
`nitrogen scavenging drug is control of blood ammonia level. Control of blood ammonia level
`
`generally refers to ammonia values within the normal range and avoidance of hyperammonemic
`
`crises, which are often defined in the art as transient ammonia values exceeding 100 ttmol/L 01'
`
`178 rig/mL accompanied by clinical signs and symptoms of hyperammonemia. Dosing of
`
`nitrogen scavenging drugs is usually based upon clinical assessment and measurement of
`
`ammonia. However, assessment of treatment effect and interpretation of ammonia levels is
`
`and are impacted by timing of the blood draw in relation to the last meal and dose of ding (see,
`
`e.g., Lee ZOIO: Lichter—Konecki 201 l; Diaz 201 l}.
`
`[0018] A random ammonia value obtained during an outpatient visit may fail to provide a
`
`reliable measure of a subject's status and the drug effect. For example, basing treatment on a
`
`blood sample taken after eating :1 meal might overestimate average daily ammonia level and
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`Attorney Ref. 7953230031502
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`result in overtreatment. Conversely. basing treatment on a blood sample taken after drug
`
`administration might underestimate average daily ammonia level and result in undertreatment. A
`
`fasting ammonia level at or near the ULN might be taken as an indication of satisfactory control
`
`without appreciating the fact that the ammonia burden during the day (average and/or highest
`
`possible value) might be significantly hig